A number of drugs have been approved to treat bipolar disorder and schizophrenia (e.g., anticonvulsants and atypical antipsychotics), and treatment of mania has been achieved with several atypical antipsychotics (e.g., risperidone, olanzapine and quetiapine). Other compounds have been used for the clinical treatment of major depressive disorder (e.g., reboxetine and desimpramine) as well as bipolar depression (quetiapine). However, improvement in therapy is still desired in terms of achieving better remission rates, more effective treatment of depression and an improved side-effect profile (e.g., reduced sedation and reduced weight gain).
For nearly 50 years, since the early 1960s, scientific and clinical investigators have sought to understand the pharmacology of tricyclic neuroleptic compounds. Numerous US and Foreign patents and scientific publications have described hundreds of different tricyclic compounds with varying antipsychotic and anti-depressive properties. In the 1960s, CH422793 a Swiss patent filed in 1961, and NL293210 a Dutch patent application filed in 1963, described tricyclic compounds. Almost forty years later, a scientific paper published in 2001 (Behavioral Approach to Nondyskinetic Antagonists: Identification of Seroquel, J. Med. Chem. 2001, 44, 372-380) described other different tricyclic compounds. Still more recently in early 2009, U.S. Pat. Nos. 7,491,715 B1 and 7,517,871 B1 were granted describing new analogues of clozapine.
Despite having a wide spectrum of pharmacological activity, current bipolar and schizophrenia drugs exhibit variable efficacy and side-effect profiles. Although some current drugs have acute efficacy, remission rates are still low. Safety and tolerability are still issues since approximately 75% of patients experience side effects, and treatment compliance is a major issue. Additionally, the mechanism of action of atypical antipsychotics is not well understood, for example, the label of Seroquel states:                “the mechanism of action of Seroquel, as with other drugs having efficacy in the treatment of schizophrenia and acute manic episodes associated with bipolar disorder, is unknown. However, it has been proposed that this drug's efficacy in schizophrenia is mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) antagonism. Antagonism at receptors other than dopamine and 5HT2 with similar receptor affinities may explain some of the other effects of Seroquel. Seroquel's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Seroquel's antagonism of adrenergic α1 receptors may explain in the orthostatic hypotension observed with, this drug.”        
Similarly, the label for olanzapine states:                “The mechanism of action of olanzapine, as with other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that this drug's efficacy in schizophrenia is mediated through a combination of dopamine and serotonin type 2 (5HT2) antagonism. The mechanism of action of olanzapine in the treatment of acute manic episodes associated with Bipolar I Disorder is unknown.        Antagonism at receptors other than dopamine and 5HT2 with similar receptor affinities may explain some of the other therapeutic and side effects of olanzapine. Olanzapine's antagonism of muscarinic M1-5 receptors may explain its anticholinergic effects. Olanzapine's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Olanzapine's antagonism of adrenergic α1 receptors may explain the orthostatic hypotension observed with this drug.”        
Thus, notwithstanding that numerous tricyclic compounds having antipsychotic and anti-depressant activity have been described and used in therapy, improved ways to treat schizophrenia and bipolar disease are still sought. Particularly, effective treatment of the depressive phase of bipolar disorder is desired and still sought, as is treatment of the manic phase, mood stabilization and maintenance for sufferers of bipolar disorder.